The bisphosponic acids and their pharmaceutically acceptable salts are an important class of medicaments that act as specific inhibitor of Osteoclast-mediated bone resorption and are useful in the treatment of bone disorders such as Paget's disease and osteoporosis. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxy-apatite found in the bone.
In particular, bisphosphonates like 3-amino-1-hydroxypropylidene-diphosphonic acid (PAMIDRONIC ACID), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONIC ACID) and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid (RISEDRONIC ACID), 1-hydroxy-3-(methylpentylamino)propylidene biphosphonic acid (IBANDRONIC ACID), 1-hydroxyethylidine bisphosphonic acid (ETIDRONIC ACID), 1-hydroxy-2-(1-imidazolyl)ethylidine bisphosphonic acid (ZOLEDRONIC ACID), 2-(imidazo[1,2-a]pyridin-2-yl)ethanoic acid (MINODRONIC ACID) 6-amino-1-hydroxyhexylidene)diphosphonic acid (NERIDRONIC ACID) have been the subject of considerable research efforts in this area.
Several methods have been reported for preparing 1-hydroxy-1,1-bisphosphonic acids. The syntheses are based on reacting a carboxylic acid with a mixture of phosphorous acid and one of the following phosphorous halides: phosphorous trichloride (PCl3), phosphorous oxychloride (POCl3), phosphorous pentachloride (PCl5), phosphorous tribromide (PBr3), phosphorous oxybromide (POBr3) or phosphorous pentabromide (PBr5), then quenching the reaction mixture with water or a nonoxidizing aqueous acid, followed by heating to hydrolyze the phosphorous intermediates to produce the final product.
U.S. Pat. No. 4,407,761 describes the synthesis of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONIC ACID) and other bisphosphonic acids. The reaction can be carried out in the presence of chlorobenzene, which does not solubilize the reaction components and serves only as a heat carrier. The reaction starts as a two-phase system, in which the melted phase gradually thickens into a non-stirrable mass. This semi-solid sticky mass finally turns into a hard, rigid material, coating the walls of the reaction vessel, fouling the reactor and preventing smooth heat transfer and complicating product work-up. Hence, this process is not suitable for commercial production.
Similar process is described in U.S. Pat. No. 5,583,122, to prepare 2-(2-pyridyl)-1-hydroxyethane-1,1-diphosphonic acid and its analogues.
U.S. Pat. No. 4,922,007 describes the use of methanesulfonic acid to overcome the non-homogeneity and solidification problems associated with the formation of intermediates during the bisphosphonation phase.
U.S. Pat. No. 5,019,651 discloses the use of methanesulfonic acid as a carrier/solvent to overcome the above mentioned solubility difficulties.
Although the problems with physical characteristics of the reaction were solved, a safety problem surfaced. Methanesulfonic acid reacts with phosphorus trichloride and under adiabatic conditions the reaction becomes self-heating at 85° C. and an uncontrolled exothermisity occurs at >140° C.
U.S. Pat. No. 5,908,959 describes a process for preparing alendronic acid comprising reacting 4-aminobutyric acid (GABA) with phosphorous acid and phosphorous trichloride in the presence of a polyalkyleneglycol or derivatives thereof. However, it was reported that large quantities of polyalkyleneglycol, as well as toluene and also an additional separation step is needed for the reaction, making it inefficient for use on a large scale. The recovery of polyalkyleneglycol in pure form for reuse is difficult.
U.S. Pat. No. 7,038,083 describes a process for preparing bishphosphonic acid using diluents other than halogenated hydrocarbons. The diluents employed in this process include aromatic hydrocarbons such as toluene, xylene and benzene and inert silicone fluids such as polymethylphenylsiloxane. This process also uses a co-diluent such as orthophosphoric acid. In this process the bisphosphonic acid is isolated from the suspension. Isolating the product from the suspension is tedious industrially and must be avoided.
WO 2006/071128 describes a process for the preparation of Risedronate sodium wherein aqueous solution of 3-pyridinyl acetic acid hydrochloride is added drop wise to phosphorus trichloride at a temperature of 0-5° C. After completion of the reaction excess phosphorus trichloride is removed by high vacuum distillation. Though, this process avoids the use of a suitable diluent, it suffers from the drawback of distilling phosphorus trichloride. The reaction mixture becomes very viscous without a solvent.
WO 98/34940 employs polyalkylene glycols as reaction solvents for synthesizing alendronic acid. However, these solvents have a high cost and are difficult to eliminate from the finished product, given their high boiling point.
WO 02/090367 teaches the use of aralkyl or alkyl ethoxylates or triglycerides such as plant or animal oils for solubilization of the reaction mixture.
US 2006/0258625 A1 describes a process for preparation of a series of bisphosphonic acids as shown below:
wherein R represents different alkyl derivative part of bisphosphonic acids, M1, M2, M3, M4 represents hydrogen or a monovalent cation. This publication describes the preparation of the bisphosphonic acid derivatives using diphenyl ether as a carrier/solvent. The solvents used in this publication are suitable for laboratory preparation of gram quantities of the product, however for commercial production it is not the preferred choice of solvent.
Therefore, a need to provide a carrier/solvent, for the manufacture of bisphosphonic acids, especially Risedronic acid, Alendronic acid, and Ibandronic acid is needed, which is cheaper, does not cause solidification of the reaction and can be easily recovered and recycled.
We have now found that, in the process of the present invention, if the reaction of carboxylic acid or its salt with phosphorous acid and a halophosphorous compound is carried out in presence of a phenolic compound, the fouling caused by solidification is reduced and results in bisphosphonates of Formula (I) in high yield and high purity.